The present invention relates to anti-inflammatory medicaments and inhibitors against increase in ocular tension caused by irradiation with lasers, which contain a specific 1,4-dihydropyridine derivative or an acid addition salt thereof.
While the administration of prostaglandin E2 (PGE2) via cornea induces inflammatory responses in the anterior uveal tissues and a temporary rise of intraocular pressure, it is known that systemic administration of a dihydropyridine Ca antagonist, nicardipine, [(Yoshihiro KAJI, Shigeyoshi HIRAKI and Hideki HIRATA: Effect of calcium antagonist on ophthalmic inflammatory response by exogenous prostaglandin E2, Journal of Japanese Ophthalmological society, 98: 825-831, 1994), (Yoshihiro KAJI, Shigeyoshi HIRAKI, Hideki HIRATA and Seiji HAYASAKA: Nicardipine inhibits acute rise of aqueous flare and intraocular pressure induced by argon laser photocoagulation, Ocular Immunol. Inflam., 4: 139-144, 1996)], nilvadipine [(Chiharu KADOI, Shigeyoshi HIRAKI, Seiji HAYASAKA and Osamu OHOTANI: Sites of disruption of the blood-aqueous barrier after application of prostaglandin E2 in pigmented rabbits, Ophthalmic Research 29: 365-373, 1996), (Xue-Yun ZHANG, Shigeyoshi HIRAKI and Seiji HAYASAKA: Nilvadipine inhibits acute rise of aqueous flare and intraocular pressure induced by prostaglandin E2 in pigmented rabbits, Ophthalmic Research 30: 135-141, 1998)] or Ca-antagonist, felodipine (Shigeyoshi HIRAKI, Xue-Yun ZHANG, Tomohiro ABE, Seiji HAYASAKA: Inhibitory effect of Ca Antagonist Felodipine on Experimental Endophthalmitis, 17th Japan Ophthalmic Pharmacological Convention, 1997, 7., Morioka) before administration of PGE2 inhibits these responses in a dose-dependent manner. Furthermore, while the argon laser is used for ophthalmic operation of angle-closure glaucoma, retinal detachment and the like, intravenous administration of Nicardipine has been reported to have inhibited experimental endophthalmitis induced by photocoagulation of iris by the argon laser (Yoshihiro KAJI, Shigeyoshi HIRAKI and Hideki HIRATA et al.: inhibitory, effect of calcium antagonist on intraocular inflammation, Abstracts of the 60th Annual Meeting of MID-Japan Ophthalmological Society, 134, 1994). It has been also reported that felodipine has an inhibitory effect on experimental endophthalmitis induced by photocoagulation of iris by the argon laser and LPS endophthalmitis induced by systemic administration of endotoxin (lipopolysaccharide=LPS) [Yoshihiro KAJI, Xue-Yun ZHANG and Seiji HAYASAKA: Inhibitory Effect of Felodipine (Ca-antagonist) on Experimental Endophthalmitis of House Rabbit, Abstracts of the 18th Annual Meeting of the Japanese ophthalmo-Pharmacological Society, 56-57, 1998].
It is already known that a certain kind of Ca antagonist, 1,4-dihydropyridine derivative and an acid addition salt thereof, are useful as a hypotensive medicament, a therapeutic medicament of angina pectoris, a cerebral circulation improving medicament, a peripheral circulation improving medicament, a renal function improving medicament, an anti-arterial sclerosis medicament, a smooth muscle relaxant, an antiallergic medicament, a therapeutic medicament of cataract, a therapeutic medicament of glaucoma (JP-A-63-225355) and an ophthalmic circulation disorder improving medicament (PCT/JP97/03866).
The 1,4-dihydropyridine derivative of the following formula (I) and an acid addition salt thereof are known to have various uses mentioned above. However, an anti-inflammatory effect and an inhibitory effect on the rise of intraocular pressure due to laser irradiation, particularly, an inhibitory effect on intraocular inflammation and rise of intraocular pressure due to laser irradiation, which is provided by topical administration of these compounds to the eye, has not been known yet.
Under the circumstances, the present inventor has closely studied the efficacy of the Ca antagonist, 1,4-dihydropyridine derivative and an acid addition salt thereof to be mentioned later, and found that these compounds have a superior anti-inflammatory effect and an inhibitory effect on the rise of intraocular pressure due to laser irradiation, and further studies have resulted in the completion of the present invention.
It is therefore an object of the present invention to provide a novel pharmaceutical use of a 1,4-dihydropyridine derivative or an acid addition salt thereof. More particularly, the present invention provides an anti-inflammatory medicament and an inhibitor of intraocular pressure rise due to laser irradiation, which contain a 1,4-dihydropyridine derivative or an acid addition salt thereof.
Accordingly, the present invention provides the following.
(1) An anti-inflammatory medicament containing, as an active ingredient, a 1,4-dihydropyridine derivative of the formula (I) 
wherein X1 and X2 are the same or different and each is hydrogen atom, fluoromethyl, fluoromethoxy, halogen, cyano or nitro, R1 is lower alkyl, R2 is acyl, alkoxycarbonyl, acylalkyl, N-alkyl-substituted carbamoylalkyl, alkoxyalkyl, alkoxycarbonylalkyl, acyloxyalkyl, nitratoalkyl, cyanoalkyl, hetero ring-alkyl, haloalkyl, alkenyl or alkynyl, A is alkylene having a carbon atom bonded with two alkyls and 5 or more carbon atoms in total, and m is an integer of 1 to 3, or an acid addition salt thereof (hereinafter sometimes to be referred as an inventive compound).
(2) The anti-inflammatory medicament of the above-mentioned (1), wherein, in the formula (I), R2 is acylalkyl, N-alkyl-substituted carbamoylalkyl, alkoxyalkyl, cyanoalkyl, hetero ring-alkyl, haloalkyl, alkenyl or alkynyl.
(3) The anti-inflammatory medicament of the above-mentioned (1), wherein, in the formula (I), R2 is alkenyl or alkynyl.
(4) The anti-inflammatory medicament of the above-mentioned (1), wherein, in the formula (I), A is alkylene having a carbon atom bonded with two alkyls and 5 to 10 carbon atoms in total.
(5) The anti-inflammatory medicament of the above-mentioned (1), wherein the acid addition salt of the 1,4-dihydropyridine derivative of the formula (I) is 3-(4-allyl-1-piperazinyl)-2,2-dimethylpropyl methyl 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate dihydrochloride.
(6) The anti-inflammatory medicament of any of the above-mentioned (1) to (5), wherein the objective disease is intraocular inflammation.
(7) The anti-inflammatory medicament of the above-mentioned (6), wherein the intraocular inflammation is caused by laser irradiation.
(8) The anti-inflammatory medicament of the above-mentioned (6) or (7), Which is for a topical administration to the eye.
(9) The anti-inflammatory medicament of the above-mentioned (8), which is in the form of an eye drop.
(10) The anti-inflammatory medicament of the above-mentioned (8), which is in the form of an eye ointment.
(11) An inhibitor of intraocular pressure rise due to laser irradiation, which contains, as an active ingredient, a 1,4-dihydropyridine derivative of the formula (I) 
wherein X1 and X2 are the same or different and each is hydrogen atom, fluoromethyl, fluoromethoxy, halogen, cyano or nitro, R1 is lower alkyl, R2 is acyl, alkoxycarbonyl, acylalkyl, N-alkyl-substituted carbamoylalkyl, alkoxyalkyl, alkoxycarbonylalkyl, acyloxyalkyl, nitratoalkyl, cyanoalkyl, hetero ring-alkyl, haloalkyl, alkenyl or alkynyl, A is alkylene having a carbon atom bonded with two alkyls and 5 or more carbon atoms in total, and m is an integer of 1 to 3, or an acid addition salt thereof.
(12) The inhibitor of intraocular pressure rise due to laser irradiation of the above-mentioned (11), wherein, in the formula (I), R2 is acylalkyl, N-alkyl-substituted carbamoylalkyl, alkoxyalkyl, cyanoalkyl, hetero ring-alkyl, haloalkyl, alkenyl or alkynyl.
(13) The inhibitor of intraocular pressure rise due to laser irradiation of the above-mentioned (11), wherein, in the formula (I), R2 is alkenyl or alkynyl.
(14) The inhibitor of intraocular pressure rise due to laser irradiation of the above-mentioned (11), wherein, in the formula (I), A is alkylene having a carbon atom bonded with two alkyls and 5 to 10 carbon atoms in total.
(15) The inhibitor of intraocular pressure rise due to laser irradiation of the above-mentioned (11), wherein the acid addition salt of the 1,4-dihydropyridine derivative of the formula (I) is 3-(4-allyl-1-piperazinyl)-2,2-dimethylpropyl methyl 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate dihydrochloride.
(16) The inhibitor of intraocular pressure rise due to laser irradiation of any of the above-mentioned (11) to (15), which is for a topical administration to the eye.
(17) The inhibitor of intraocular pressure rise due to laser irradiation of the above-mentioned (16), which is in the form of an eye drop.
(18) The inhibitor of intraocular pressure rise due to laser irradiation of the above-mentioned (16), which is in the form of an eye ointment.
(19) A method for preventing or treating inflammation, which method comprises administering an effective amount of the 1,4-dihydropyridine derivative of the formula (I) or an acid addition salt thereof of the above-mentioned (1).
(20) A method for inhibiting rise of intraocular pressure due to laser irradiation, which method comprises administering an effective amount of the 1,4-dihydropyridine derivative of the formula (I) or an acid addition salt thereof of the above-mentioned (11).
(21) Use of the 1,4-dihydropyridine derivative of the formula (I) or an acidaddition salt thereof of the above-mentioned (1) for the production of an anti-inflammatory medicament.
(22) Use of the 1,4-dihydropyridine derivative of the formula (I) or an acid addition salt thereof of the above-mentioned (11) for the production of an inhibitor of intraocular pressure rise due to laser irradiation.
(23) A pharmaceutical composition for preventing or treating inflammation, which composition contains the 1,4-dihydropyridine derivative of the formula (I) or an acid addition salt thereof of the above-mentioned (1), and a pharmaceutically acceptable carrier.
(24) A pharmaceutical composition for inhibiting rise of intraocular pressure due to laser irradiation, which composition contains the 1,4-dihydropyridine derivative of the formula (I) or an acid addition salt thereof of the above-mentioned (11) and a pharmaceutically acceptable carrier.
(25) A commercial package comprising a pharmaceutical composition of the above-mentioned (23) and a written matter associated therewith, the written matter stating that the pharmaceutical composition can or should be used for preventing or treating inflammation.
(26) A commercial package comprising a pharmaceutical composition of the above-mentioned (24) and a written matter associated therewith, the written matter stating that the pharmaceutical composition can or should be used for inhibiting rise of intraocular pressure due to laser irradiation.